Effects Of Perospirone Research Articles

Antihyperalgesic effects of intrathecal perospirone in a rat model of neuropathic pain

The descending serotonergic pathway, from the brainstem to spinal cord, modulates various aspects of pain processing. The spinal 5-hydroxytryptamine (5-HT)1A and 5-HT2A receptors play pivotal roles in pain modulation. Perospirone is a novel atypical antipsychotic that serves as a 5-hydroxytryptamine (5-HT)1A receptor agonist, a 5-HT2A receptor antagonist, and a dopamine D2 receptor antagonist. Little is known about the effect of perospirone on pain transmission. Here, we explored whether perospirone attenuated neuropathic and inflammatory pain in the spinal cord. A chronic constriction injury to the sciatic nerve was induced in male Sprague-Dawley rats. We evaluated the effects of intrathecal administration of perospirone (10, 20, or 40 μg) on mechanical and cold hyperalgesia using the electronic von Frey and cold plate tests, respectively. Normal rats were assessed in terms of inflammatory nociception using the formalin test and for motor coordination employing the rotarod test. To define the mechanism underlying the action of perospirone, the effects of intrathecal pretreatment with the 5-HT1A receptor antagonist WAY-100635, the 5-HT2A/2C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-aminopropane (DOI), and the dopamine D2 receptor agonist sumanirole on perospirone action were examined using the electronic von Frey test and cold plate test. Perospirone dose-dependently alleviated mechanical and cold hyperalgesia, but not inflammatory nociception in the spinal cord, and affected motor coordination. WAY-100635 reversed the antihyperalgesic action of perospirone significantly, but neither DOI nor sumanirole exhibited such an effect. We conclude that perospirone attenuates mechanical and cold hyperalgesia principally via 5-HT1A receptor activation in the spinal cord, and the agent is a promising novel candidate for neuropathic pain relief.

Beneficial effects of perospirone on aggressive behavior associated with dementia

The aim of this study was to assess the efficacy of the serotonin-dopamine antagonist perospirone in treating aggressive and agitated behavior in patients with dementia. Six patients were referred to the outpatient clinic of Ishizaki Hospital and were followed for 6 weeks. Their psychiatric diagnoses were made using the DSM-IV. Their behavioral symptoms and degrees of cognitive impairment were measured using the Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD) and the Mini-Mental Examination State. The changes in BEHAVE-AD scores were investigated. Maximum benefit was achieved at a mean perospirone dose of 9.0 mg/day. No patient experienced severe adverse effects. Post-hoc analysis showed significant improvement in the total BEHAVE-AD and aggressiveness subscale scores within 2 weeks. This study suggests that perospirone is effective in improving aggressive and agitated behavioral symptoms in demented patients and is safe to use in elderly patients.

In vitro drug-drug interactions with perospirone and concomitantly administered drugs in human liver microsomes.

In vitro metabolism studies were conducted to assess drug-drug interactions between perospirone, an antipsychotic agent, and concomitantly administered drugs--biperiden, flunitrazepam, haloperidol, and diazepam--using human liver microsomes. The metabolism of perospirone in the presence of 100 microg/ml drugs was decreased to 45-73% of that in their absence, whereas no effects were observed with any of the drugs at 1 microg/ml or lower. The effects of perospirone on the metabolism of concomitantly administered drugs were also assessed, and no inhibitory effect was observed. Thus, the metabolism of perospirone and concomitantly administered drugs did not demonstrate any marked mutual inhibition in the human liver microsomes. On the other hand, the perospirone metabolism was markedly reduced by ketoconazole indicating a major role for CYP 3A4. Based on the inhibition constant (Ki) for perospirone metabolism and the plasma unbound concentration of ketoconazole, in vivo perospirone clearance was estimated to be reduced to 64-90% of the control level. Thus careful attention should be paid to the possibility of increase in unchanged perospirone concentration when perospirone is co-administered with drugs that are known as CYP3A4 inhibitors, including macrolide antibiotics and other imidazole antifungals.

Effects of Perospirone, a Novel 5-HT 2 and D 2 Receptor Antagonist, on Fos Protein Expression in the Rat Forebrain

The effects of perospirone, a novel 5-HT 2 and D 2 receptor antagonist, on Fos protein expression in the nucleus accumbens (NA) and dorsolateral striatum (DLSt) were compared with those of typical (i.e., haloperidol and fluphenazine) and atypical (i.e., clozapine and risperidone) antipsychotics using immunohistochemical techniques in rats. Perospirone and other antipsychotics tested at doses that exerted D 2 blocking actions increased Fos-like immunoreactivity both in the NA and DLSt. However, the levels of Fos expression in the DLSt induced by perospirone and clozapine were less than those induced by haloperidol and fluphenazine. When compared the differences in numbers of Fos-positive neurons between in the NA and DLSt, perospirone, clozapine, and risperidone preferentially increased Fos expression in the NA. These findings suggest that perospirone has a preferential action on the mesolimbic (vs. nigrostriatal) dopaminergic system in inducing Fos protein in the rat brain, which may be related to its atypical antipsychotic properties.

P-234 - Effects of perospirone(SM-9018), a novel 5-HT2 and D2 antagonist, on human D2 and D4 receptors in CHO cells

P-234 - Effects of perospirone(SM-9018), a novel 5-HT2 and D2 antagonist, on human D2 and D4 receptors in CHO cells